No abstract

The intestinal environment harbors a large number of activated T cells, which are potentially inflammatory. To prevent inflammatory responses, intestinal T cells are controlled by various tolerogenic mechanisms, including T cell apoptosis. We investigated the expression mechanism and function of the purinergic receptor P2X7 in contraction of intestinal CD4+ effector T cells. We found that P2X7 up-regulation on CD4+ effector T cells is induced by retinoic acid through retinoic acid receptor α (RARα) binding to an intragenic enhancer region of the P2rx7 gene. P2X7 is highly expressed by most intestinal αβ and γδ T cells, including Th1 and Th17 cells. The intestinal effector T cells are effectively deleted by P2X7 activation-dependent apoptosis. Moreover, P2X7 activation suppressed T cell-induced colitis in Rag1−/− mice. The data from vitamin A-deficient and P2rx7−/− mice indicate that the retinoic acid-P2X7 pathway is important in preventing aberrant build-up of activated T cells. We conclude that retinoic acid controls intestinal effector T cell populations by inducing P2X7 expression. These findings have important ramifications in preventing inflammatory diseases in the intestine.

The intestinal immune system is regulated by microbes and their metabolites. The roles of gut microbial metabolites in regulating intestinal inflammation and tumorigenesis are incompletely understood. We systematically studied the roles of short-chain fatty acids (SCFAs) and their receptors (GPR43 or GPR41) in regulating tissue bacterial load, acute versus chronic inflammatory responses, and intestinal cancer development. SCFA receptor-, particularly GPR43-, deficient mice were defective in mounting appropriate acute immune responses to promote barrier immunity, and developed uncontrolled chronic inflammatory responses following epithelial damage. Further, intestinal carcinogenesis was increased in GPR43-deficient mice. Dietary fiber and SCFA administration suppressed intestinal inflammation and cancer in both GPR43-dependent and independent manners. The beneficial effect of GPR43 was not mediated by altered microbiota but by host tissue cells and hematopoietic cells to a lesser degree. We found that inability to suppress commensal bacterial invasion into the colonic tissue is associated with the increased chronic Th17-driven inflammation and carcinogenesis in the intestine of GPR43-deficient mice. In sum, our results reveal the beneficial function of the SCFA-GPR43 axis in suppressing bacterial invasion and associated chronic inflammation and carcinogenesis in the colon.